Tranquilizers

ABSTRACT

Tranquilizing agents for warm-blooded animals corresponding to the formula   WHERE Y can be -(CH2)n- or   WHERE R can be hydrogen or methyl; Z can be pyridyl, or the group   WHEREIN R1 is hydrogen, methoxy, chloro-, nitro-, or acetamido; or Z can be 3,4-methylenedioxophenyl.

United States Patent [191 Wehrmeister 11] 3,886,147 [1451 May 27, 1975TRANQUILIZERS [75] Inventor: Herbert L. Wehrmeister, Terre Haute, Ind.

[73] Assignee: Commercial Solvents Corporation,

Terre Haute, Ind.

[22] Filed: May 31, 1974 [21] Appl. No.: 475,064

Related US. Application Data [62] Division of Ser. No. 312,075, Dec. 4,1972,

abandoned.

[56] References Cited UNITED STATES PATENTS 11/1970 Koch 424/246 12/197]McFarland et a1. 260/240 D 1/1972 Koch 260/240 D Primary Examiner-ArthurP. Demers Attorney, Agent, or FirmRobert H. Dewey; Howard E. Post [57ABSTRACT Tranquilizing agents for warm-blooded animals corresponding tothe formula N c CH3 Z-Y-C where Y can be (CH or 1 -CH=C-R,

where R can be hydrogen or methyl; Z can be pyridyl, or the groupwherein R is hydrogen, methoxy, chloro-, nitro-, or acetamido; or Z canbe 3,4-methylenedioxophenyl.

3 Claims, No Drawings TRANQUILIZERS This is a division of applicationSer. No. 312,075, filed Dec. 4, 1972, now abandoned.

SUMMARY OF THE INVENTION Z-Y-C \N (2 CH are central nervous systemdepressants which are useful in the calming of warm-blooded animals. Inthe formula, Y can be (CH )n-, where n is 1 or 2, or

where R can be hydrogen or methyl.

Z can be pyridyl or the group wherein R is hydrogen, methoxy, ch1oro-,nitro-, or acetamido-; or Z can be 3,4-methylenedioxopheny1.

DETAILED DISCUSSION The compounds of the present invention have beenfound to exert a depressant action on the central nervous system whentested under standard and accepted pharmacological procedures, inanimals, such as mice and rats. They are, therefore, deemed to possessutility in experimental and comparative pharmacology and are of value totreat conditions in animals, such as valuable domestic animals, and inlaboratory animals, such as mice, rats and the like, responsive totreatment with central nervous system depressant agents. Specifically,the compounds may be employed to induce a calming effect in animals.

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects were tested by threedifferent tests. In one, the oral toxicity was determined byadministration to a group of laboratory mice. A trained observer watchedthe mice closely for several hours and noted decreased motor activity.The second test was the so-called "jiggle cage method, a techniquedescribed by R. A Turner, Screening Methods in Pharmacology, page 89,published 1965, Academic Press, New York, and summarized in Example 1.The third test was that described by Horn, Biometrics, 12:31 1 (1956).In this test, laboratory mice received the test compound (2 mice perdose level) at one-half log-dosage intervals by intravenous injection.The animals were observed by trained observers and pharmacological signsof tranquilization were noted. The median lethal dose (LD and the medianeffective dose (MED were estimated. The safety factor was taken as theratio of LD50/MED50.

The compounds ofthis invention are active as central nervous systemdepressants at a dose of about 0.01 to about 1000 mg/kg. When thecompounds are administered intravenously, a dose within the range 1.8-mg/kg is generally preferred, depending on the compound. When thecompounds are administered orally, a dose within the range of 10-500mg/kg is generally preferred, depending on the compound.

The thiazolines of the present invention are derivatives of2,4,4-trimethy1-2-thiazoline which can be readily prepared by knownmethods, e.g. the method of G. R. I-Iandrick et at., J. Med. Chem. 8,762 (1965). In general, the compounds are readily prepared by reacting2,4,4-trimethyl-2-thiazoline with the appropriate aldehyde following theprocedure of H. L. Wehrmeister, J. Org. Chem. 27, 4418 (1962) forpreparing analogous oxazolines. The compounds of examples 7 and 8 areexceptions, however. Their preparation is given in the examples.

Thiazolines are weakly alkaline and form salts with most acids. Many ofthese salts are water-soluble and this invention contemplates theadministration of pharmaceutically acceptable salts of thesethiazolines.

The invention will be better understood with reference to the followingexamples. It is understood, however, that the examples are intended forillustration only and it is not intended that the invention be limitedthereby.

EXAMPLEl 2-(2-p-Chloropheny1ethenyl)-4,4-dimethyl-2- thiazoline (P-1896)was synthesized from pchlorobenzaldehyde and2,4,4-trimethyl-2-thiazoline, which is commercially available, by thefollowing procedure:

A stirred mixture of 42.2 g (0.3 mole) pchlorobenzaldehyde, 39.2 g (0.3mole) 2,4,4-trimethy1- 2-thiazoline, and 1 g sodium bisulfate in 100 mlxylene was heated at reflux under a 4-bulb Snyder column, waterseparator (20 ml) and reflux condenser with azeotropic removal of 5.4 mlwater in 4% hours (t=-159).

The pot mixture was then filtered at room temperature through filter aidand the filter cake was washed with 25 ml of warm xylene. The filtrateplus wash was cooled in a refrigerator. The solid that precipitated wascollected by filtration,'washed with 25 ml xylene and dried in a vacuumdesiccator, m.p. 84-86.

Anal. Calcd. for C H ClNS: C, 62.01; H, 5.60; N, 5.56; C1, 14.08; S,12.73. Found: C, 62,41, 62.49; H, 5.66, 5.78; N, 5.67, 5.33; Cl, 13.81;S, 14.18, 12.61.

The nuclear magnetic resonance (nmr) spectrum and the IR spectrum wereconsistent with the structure assigned. Evidence from nmr indicates thatthe olefinic hydrogens are probably trans.

The acute LD by oral administration to mice was 1140 i 42 mg/kg. The LDwas 1000 mg/kg and the LD was 2000 mg/kg. Animals receiving the compoundwere strongly tranquilized. The compound was tested for tranquilizingactivity by the method of Horn. The compound was dissolved inpolyethylene glycol 300 and was administered intravenously at dosagelevels of 10, 32, 100 and 320 mg/kg. to mice, two animals per dosagelevel. The dilution was such that each animal received a dose of 1 ml ofsolution per kilogram of body weight. A trained observer watched theanimals for evidence of central nervous system depressant activity ingeneral and tranquilizing activity in particular. The dosage at whichthese signs became apparent was reported as the median effective dose(MED Also, the LD by intravenous administration was estimated and thesafety factor, the ratio of LD50/MED was determined. For P-l 896, the LDby intravenous administration was greater than 320.0 mg/kg. The medianeffective dose for tranquilization was 5.6 (l.8-l8.0) mg/kg, and thesafety factor was greater than 57.0.

EXAMPLE 2 The experiment of Example 1 was repeated in all essentialdetails except that p-methoxybenzaldehyde was substituted forp-chlorobenzaldehyde. The product thereby obtained was 4,4-dimethyl-2-(2-pmethoxyphenylethenyl)-2-thiazoline (P-l 874).

The acute LD of this compound by oral administration to mice wasdetermined to be 2400 35 394 mg/kg. The LD was 1000 mg/kg and the LD wasless than 5000 mg/kg. Animals receiving the compound were tranquilized.

The product was tested for tranquilizer activity by the jiggle cagemethod of R. A. Turner, Screening Methods in Pharmacology, page 89,Academic Press, New York (1965). In this method, a cage is suspendedfrom a rope and rests lightly on a pneumatic bed connected by a tube toa transducer. Activity by an animal (the rat, in these tests) in thecage results in changes of pressure on the pneumatic bed. The transducerchanges these pressure variations to electrical impulses which arecontinuously recorded on a chart, making it possible to quantitate theamount, severity and frequency of the movement. The rats were fasted for48 hours prior to testing to insure a high level of activity in the testcage.

At the time of the test, each rat was weighed and placed in the jigglecage. All activity of the rat was measured by the pneumatic sensor. Therat was then removed from the cage and closed with either a testmaterial, negative control material, or standard material.

The rat was then placed in its original cage for 30 minutes. Followingthis, the rat was returned to the jiggle cage for minutes and allactivity recorded. The test, control, and standard material were givento the rats via stomach tube.

The above compound (1 -1874) was tested on three rats using the aboveprocedure. With each run a standard, chlordiazepoxid hydrochloride, andnegative control test were performed on at least one rat. Polyethyleneglycol 400 was used as the solvent in each case. The standard and alltest substances were administered by stomach tube at a dosage level of 1mg per 100 grams of body weight.

The results obtained are as followsz ACTIVITY DATA Average PolyethyleneGlycol 400 5 ml dist. water used as vehicle in all conditions.

ACTIVITY RESULTS No. of Corrected* Activity Animals Condition ActivityCoefficient 1 Standard 0.261 0.086 3 Test l 3 1 .216 1 Positive .347

Control *Activity After Material Dose Activity Before Material Dose**Corrected Activity Positive Control Corrected Activity Condition Thehigher the score, the more tranquilizing activity exhibited.

The product, P-l874, was additionally tested for tranquilizing activityby the method of Horn, described in Example 1. The LD by intravenousadministration was 180.0 (56.0-560.0) mg/kg. The median effective dosefor tranquilization was 32.0 mg/kg (10.0-100.0) and the safety factorwas 5.6.

EXAMPLE 3 4,4-Dimethyl-2-(2-m-nitrophenylethenyl)-2- 4O thiazoline (P-l897) was prepared by the process of Example 1 except that2-nitrobenzaldehyde was substituted for p-chlorobenzaldehyde.

The acute LD by oral administration to mice was determined to beapproximately 1220 mg/kg. The LD was 1000 mg/kg and the LD was 1500mg/kg. The

animals receiving the compound appeared to be hypersensitive suggesingthat the compound was a nervous system irritant at doses over 1000mg/kg.

The product was additionally tested by the method of I-Iorn. The LD byintravenous administration was 320 mg/kg and the median effective dosefor tranquilization was 10.0 (3.2-32.0) mg/kg. The safety factor was10.0.

EXAMPLE 4 4,4-Dimethyl-2-[2-(3,4-methylenedioxyphenyl)-ethenyl]-2-thiazoline (P-1908) was prepared by the method of Example 1except that 3,4-methylenedioxybenzaldehyde was substituted forpchlorobenzaldehyde.

The acute LD by oral administration to mice was determined to beapproximately 3000 mg/kg. The LD was 1400 mg/kg and the LD was 5000mg/kg. Animals receiving the compound were tranquilized.

The product was additionally tested for tranquilizing activity by themethod of Horn. Itjwas administered as a suspension in 0.5% methylcellulose in water. The LD by intravenous administration was 180.0(56.0-560.0) mg/kg. The median effective dose for tranquilization was10.0 (3.232.0) mg./kg and the safety factor was 18.0.

EXAMPLE 5 4,4-Dimethyl-2-[2-( 3-pyridyl)ethenyl l-2-thiazoline (P-1903)was prepared from pyridine-3- carboxaldehyde and2,4,4-trimethyl-2-oxazoline according to the method of Example 1.

The acute oral toxicity was determined by administration to mice. The LDwas approximately 3000 mg/kg. The LD was approximately 1400 mg/kg andthe LD was greater than 5000 mg/kg. Animals receiving the compound weretranquilized.

The product was additionally tested by the method of l-lorn. The LD byintravenous administration was 180.0 (56.0-5 60.0) The median effectivedose for tranquilization was 10.0 (31.2-32.0) mg/kg, and the safetyfactor was 18.0.

EXAMPLE 6 2-(2-p-acetamidophenylethenyl)-4,4-dimethyl-2- thiazoline(P--1909) was prepared from pacetamidobenzaldehyde and2,4,4-trimethyl-2- thiazoline according to the method of Example 1.

The acute oral toxicity was determined by administration to mice. The LDwas 1500 i 246 mg/kg. The LD was approximately 500 mg/kg and the LD was3000 mg/kg. Animals receiving the product were mildly tranquilized. Thecompound was also tested in accordance with the method of Horn. The LDby intravenous administration was 180.0 mg/kg (560-5600). The medianeffective dose for tranquilization was 18.0 mg/kg (5.6-56.0) and thesafety factor was 10.0.

EXAMPLE 7 4,4-Dimethyl-2-(p-methoxybenzyl)-2-thiazoline (P-l 881) wassynthesized as follows. To a 500 ml flask there was charged4-methoxyphenylacetonitrile 25.34 g (0.17 mole) dissolved in 200 m1xylene. The flask was equipped with a thermometer, a gas inlet tubeconnected to a hydrogen sulfide supply, a reflux condenser, droppingfunnel and a stirrer. A solution of 2,2- dimethylaziridine 12.1 g (0.17mole) dissolved in xylene, to 60 ml was placed in the dropping funnel.

Hydrogen sulfide was passed into the nitrile solution with stirring atroom temperature and after a few minutes, drop-wise addition of theaziridine was started and continued until the temperature started torise. It was then interrupted until the temperature began to drop, thenaddition of the aziridine was gradually completed. After the temperaturebegan to drop, the hydrogen sultide was turned off and the solution washeated at 145l47 for about 10 hours.

The cooled reaction product was washed with water, dried over sodiumsulfate and distilled through a inch Vigreux column. The fractiondistilling at 96l at about 0.34-0.40 mm was dissolved in benzene, andextracted with dilute hydrochloric acid solution. The extract wasneutralized with aqueous sodium bicarbonate solution and this mixturewas extracted with benzene. The benzene solution was dried over so diumsulfate and evaporated.

The residue was distilled through a 15 inch Vigreux column and thefraction distilling at 118, 0.34 mm, was selected as the product. Itanalyzed 66.31% carbon, 7.20% hydrogen, 5.80% nitrogen, and 13.46%sulfur. These values were in good agreement with the calculated valuesfor the expected product, viz. carbon 66.35%, hydrogen 7.28%, nitrogen5.95%, and sulfur 13.63%. The infra-red absorption spectrum wasconsistent with the expected structure.

The acute oral toxicity was determined by administration to mice. The LDwas 740 i 127 mg/kg. The LD was 400 mg/kg and the LD was 1000 mg/kg.Animals receiving from 200-800 mg/kg were tranquilized.

The product was tested for tranquilizing activity by the method of Horn.The LD by intravenous administration was 180.0 (560-5600) mg/kg. Themedian effective dose for tranquilization was 18.0 (5.6-5 6.0) mg/kg andthe safety factor was 10.0.

EXAMPLE 8 2-Benzyl-4,4-dimethyl-2-thiazoline (P-1880) was made by thefollowing synthesis. 2-Amino-2-methyl-lpropanol was reacted withsulfuric acid to form the acid ester and internal salt. This product wasdropped into sodium hydroxide solution thereby forming ca c CH2 whichvolatilized and was recovered by condensation. This compound was thentreated with phenylacetonitrile and hydrogen sulfide to form P-1880.

The acute LD by oral administration to mice was 740 i 127 mg/kg. Animalsreceiving the compound were moderately tranquilized.

The compound was additionally tested by the method of Horn. The LD byintravenous administration was 180.0 (56.0560.0) mg/kg. The medianeffective dose for tranquilization was 32.0 (10.0-100.0) mg/kg and thesafety factor was 5.6.

EXAMPLE 9 4,4-Dimethyl-2-(2-p-nitrophenylethenyl)-2- thiazoline (P-l910)was prepared by reacting pnitrobenzaldehyde with2,4,4-trimethyl-2-thiazoline. The boiling point of the product wasl74202 at 0.2 mm; the melting point was l24l27 and the nmr spectrum wasconsistent with the proposed structure. The oral LD by administration tomice was greater than 3000 mg/kg.

The compound was tested for tranquilizing activity by the method of How.The LD by intravenous administration to mice was 180.0 mg/kg(56.0-5600). The median effective dose for tranquilization was 10.0mg/kg (3.2-32.0), and the safety factor was 18.0.

EXAMPLE l0 2-(Z-p-methoxyphenylethenyl)-2-thiazoline (P- 1917) wasprepared by reacting p-anisaldehyde with 2,4,4-trimethyl-Z-thiazoline.The product had a melting point of 9698 and the nmr spectrum wasconsistent with the proposed structure.

The compound was tested. for tranquilizing activity by the method ofHorn. The LD by intravenous administration to rats was 180.0 mg/kg(560-5600). The median effective dose for tranquilization was 5.6 mg/kg(l.8-18.0) and the safety factor was 32.0.

I claim:

mula:

l. A thiazoline compound corresponding to the for- Z-Y-C S CH N C (CH3)acetamidophenyl.

UNITED STATES PATENT GFFICE CERTIFICATE OF CORRECTIGN Patent No.3,886,147 Dated Maw 27, 1975 Q lnv nt fl Herbert L. Wehrmeister It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 2, line 60, "C, 62,41" should read -C, 62.41--

Column 3, line 29, "2400 35 394" should read -2400 1' 394-- Signed andScalrd this tenth Day Of February 1976 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'Patentsand Trademarks

1. A THIAZOLINE COMPOUND CORRESPONDING TO THE FORMULA:
 2. The compoundof claim 1 wherein Z is p-methoxyphenyl.
 3. The compound of claim 1wherein Z is p-acetamidophenyl.